Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 215 million cases and 438 thousand deaths each year. Malaria disproportionately affects sub-Saharan Africa, where 88% of cases and 90% of deaths occur. There has recently been a dramatic increase in the scale up of control interventions and reduction in the burden of malaria across Africa. However, progress has not been uniform, and in fact has been slowest in countries with the highest burden, such as Uganda. Our program called ?PRISM? has been based in Uganda, representing the East African region for the International Centers of Excellence for Malaria Research network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM we have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies in three regions with differing transmission intensities. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved our understanding of the epidemiology of malaria in Uganda and of the impact of control interventions. In this renewal application we propose to continue key components of our malaria surveillance work, but to expand our scope to address more fundamental questions about interactions between the parasite, mosquito vector, and human host. More intensive longitudinal evaluations will be conducted and cutting edge molecular studies will be added to better measure exposure to infective bites; more sensitively identify bloodstream infections; characterize parasite, vector, and human genetic factors that impact on malaria; and assess impacts of these factors on infectivity and transmission. The program will consist of three research projects linked together in an integrated manner to maximize scientific discovery. Research project 1 (Resistance project) will use samples collected over time at multiple sites to characterize the evolution of phenotypic and genotypic markers of drug and insecticide resistance and assess the impacts of these markers on malaria transmission. Research project 2 (Epidemiology project) will use longitudinal samples from cohorts to characterize factors that determine whether sporozoite inoculation results in the establishment of blood stage infection and characterize factors affecting the duration, density, and clinical consequences of blood stage infections. Research project 3 (Transmission project) will use cohort samples to determine factors associated with gametocyte production and development, evaluate infectivity of the human host to mosquito vectors, and characterize the human infectious reservoir. These highly interrelated projects will be conducted in settings with varied malaria epidemiology and differing population level control intervention to provide critical information needed to optimize strategies for the control and ultimate elimination of malaria in Uganda.